Differential Connectivity of Perirhinal and Parahippocampal Cortices Within Human Hippocampal Subregions Revealed by High-Resolution Functional Imaging

6550 • The Journal of Neuroscience, May 9, 2012 • 32(19):6550–6560

Behavioral/Systems/Cognitive Differential Connectivity of Perirhinal and Parahippocampal Cortices within Human Hippocampal Subregions Revealed by High-Resolution Functional Imaging

Laura A. Libby,1 Arne D. Ekstrom,1,3 J. Daniel Ragland,2 and Charan Ranganath1,3 Departments of 1Psychology and 2Psychiatry and Behavioral Sciences and 3Center for Neuroscience, University of California, Davis, Davis, CA 95616

Numerous studies support the importance of the perirhinal cortex (PRC) and parahippocampal cortex (PHC) in episodic memory. Theories of PRC and PHC function in humans have been informed by neuroanatomical studies of these regions obtained in animal tract-tracing studies, but knowledge of the connectivity of PHC and PRC in humans is limited. To address this issue, we used resting-state functional magnetic resonance imaging to compare the intrinsic functional connectivity profiles associated with the PRC and PHC both across the neocortex and within the subfields of the hippocampus. In Experiment 1, we acquired standard-resolution whole-brain resting-state fMRI data in 15 participants, and in Experiment 2, we acquired high-resolution resting-state fMRI data targeting the hippocampus in an independent sample of 15 participants. Experiment 1 revealed that PRC showed preferential connectivity with the anterior hippocampus, whereas PHC showed preferential connectivity with posterior hippocampus. Experiment 2 indicated that this anterior–posterior functional connectivity dissociation was more evident for subfields CA1 and subiculum than for a combined CA2/ CA3/dentate gyrus region. Finally, whole-brain analyses from Experiment 1 revealed preferential PRC connectivity with an anterior temporal and frontal cortical network, and preferential PHC connectivity with a posterior medial temporal, parietal, and occipital network. These results suggest a framework for refining models of the functional organization of the human medial temporal lobes in which the PRC and PHC are associated with distinct neocortical pathways that, in turn, may differentially interact with regions along the anterior–posterior axis of the hippocampus.

Introduction Burwell and Amaral, 1998a,b) (see Fig. 1A,B). However, because The medial temporal lobe (MTL) is a key component of a anatomical tracer studies are not feasible in humans, it is un- network of cortical and subcortical areas that are critical for known whether the human PRC and PHC exhibit differential memory (Squire and Zola-Morgan, 1991; Eichenbaum, 2006). connectivity with higher neocortical regions and with hippocam- These areas include the perirhinal cortex (PRC), parahip- pal subfields. pocampal cortex (PHC), entorhinal cortex (ERC), and hip- Functional connectivity analysis of blood oxygenation level- pocampal formation (HF), which contains subfields cornu dependent (BOLD) functional magnetic resonance imaging (fMRI) ammonis 1–3 (CA1, CA2, CA3), dentate gyrus (DG), and provides a noninvasive means to assess in vivo large-scale connectiv- subiculum (Lorente de No, 1934; Duvernoy and Bourgouin, ity in the human brain (Raichle et al., 2001; Biswal et al., 2010). 1998). Lesion and human neuroimaging studies suggest distinct Coherent low-frequency signal fluctuations recorded during roles for the PRC and PHC in memory formation and retrieval, resting-state fMRI reflect broad networks of brain regions linked although it is not clear how best to characterize these roles by direct and indirect anatomical connections (Vincent et al., (Brown and Aggleton, 2001; Davachi, 2006; Eichenbaum et al., 2007; Skudlarski et al., 2008; Greicius et al., 2009; Honey et al., 2007; Ekstrom and Bookheimer, 2007; Litman et al., 2009; Ran- 2009; Barnes et al., 2010). To our knowledge, only one previous ganath, 2010). Some clues come from tract-tracing studies in study (Kahn et al., 2008) has specifically examined intrinsic func- rodents and monkeys suggesting that PRC and PHC differ in tional connectivity with human PHC and PRC. The posterior their anatomical connectivity with sensory and association areas hippocampus and PHC showed significant functional connectiv- and with hippocampal subfields (Suzuki and Amaral, 1994a,b; ity with retrosplenial cortex and medial and ventrolateral parietal areas, whereas anterior hippocampus and a combined PRC–ERC region showed significant functional connectivity with anterior Received July 20, 2011; revised Feb. 23, 2012; accepted March 18, 2012. Authorcontributions:L.A.L.,A.D.E.,J.D.R.,andC.R.designedresearch;L.A.L.performedresearch;A.D.E.contrib- and ventrolateral temporal cortex. However, the spatial resolu- uted unpublished reagents/analytic tools; L.A.L. analyzed data; L.A.L., A.D.E., J.D.R., and C.R. wrote the paper. tion of standard whole-brain fMRI cannot resolve BOLD signal ThisworkwassupportedbyNationalInstitutesofHealthGrantsR01MH084895andRO1MH83734andtheAlfred differences across different HF subfields, which have dimensions T. Sloan Foundation. We gratefully acknowledge Dr. Steve Petersen for the helpful suggestions. on the order of millimeters and may contain discrete connectivity Correspondence should be addressed to Laura A. Libby, University of California, Davis, Center for Neuroscience, 1544 Newton Court, Davis, CA 95616. E-mail: [email protected]. patterns not detectable at the larger scale. Newly developed high- DOI:10.1523/JNEUROSCI.3711-11.2012 resolution fMRI techniques centered on the MTL have revealed Copyright © 2012 the authors 0270-6474/12/326550-11$15.00/0 distinct patterns of activity in different HF subfields during task Libby et al. • Human PRC and PHC Functional Connectivity J. Neurosci., May 9, 2012 • 32(19):6550–6560 • 6551

Figure 1. Medial temporal lobe anatomical parcellation. A, B, Model of cortical and hippocampal connectivity of PRC and PHC with neocortex (A) and hippocampal subfields (B) based on animal anterograde and retrograde tracer studies (Burwell, 2000). C, Examples of individually defined ROIs for PRC and PHC for a single subject in Experiment 1. D, Examples of individually defined ROIs for PRC, PHC, ERC, CA1, CA2/CA3/DG, and subiculum in Experiment 2.

(Ekstrom et al., 2009; Suthana et al., 2010; Dudukovic et al., slices; voxel size, 1 ϫ 1 ϫ 1 mm). Images sensitive to BOLD contrast were 2011), but this method has not been applied to questions about acquired using a gradient echo planar imaging (EPI) sequence (210 time resting-state functional connectivity in the MTL. points; matrix size, 64 ϫ 64; TR, 2000 ms; TE, 25 ms; FOV, 220; 34 slices, ϫ ϫ Here, we report results from two experiments examining in- interleaved; voxel size, 3.4375 3.4375 3.4 mm) for 7 min while trinsic functional networks correlated with signal in PHC and participants rested with eyes open and lights on a low setting. The FMRI Expert Analysis Tool in the FMRIB Software Library (FSL PRC seed regions. In Experiment 1, we used standard-resolution version 4.1; www.fmrib.ox.ac.uk/fsl) was used for fMRI analysis. Brain resting-state fMRI to identify distributed whole-brain networks volumes were extracted from full-head functional and structural images. showing preferential functional connectivity with individually Functional images were motion corrected and bandpass filtered for fre- anatomically defined PHC and PRC seed regions. In Experiment quencies of 0.01–0.1 Hz. To prepare volumes for time course extraction, 2, we used high-resolution resting-state fMRI to characterize functional images were registered to each participant’s MPRAGE image functional connectivity between PHC and PRC seeds with ante- using a rigid-body transformation (df ϭ 6) using FMRIB’s Linear Image rior versus posterior sections of HF subfields (subiculum, CA1, Registration Tool (FLIRT) (Jenkinson and Smith, 2001; Jenkinson et al., and CA2/CA3/dentate gyrus). 2002). Demarcations of anatomical regions of interest. Boundaries between Materials and Methods PHC and PRC were defined manually on individual participant Participants native-space MPRAGE images in FSLView using criteria outlined by Two independent samples of 15 young, healthy adults underwent whole- Insausti et al. (1998), Duvernoy and Bourgouin (1998) and Zeineh et brain (eight females) or high-resolution (eight females) fMRI scanning. al. (2001). PHC regions of interest (ROIs) extended from the first slice Participants were excluded for current use of psychoactive drugs and containing the body of the hippocampus to the slice halfway through history of head trauma or neurologic or psychiatric illness. Informed the lateral ventricles in the anterior–posterior direction, and from the consent was obtained before MRI scanning. collateral sulcal fundus to the most medial vertex of the parahippocampal gyrus in the lateral–medial direction. PRC ROIs extended from the Experiment 1: whole-brain imaging most anterior slice of the collateral sulcus to the last slice containing the Data acquisition and preprocessing. Participants underwent scanning at hippocampal head in the anterior–posterior direction and across both the UC Davis Imaging Research Center on a 3T Siemens Trio system banks of the collateral sulcus in the lateral–medial direction. PHC and (Siemens) with an eight-channel phased-array head coil (N ϭ 15; two PRC ROIs for right and left hemispheres were created separately by man- subjects were scanned after a system upgrade to the Total imaging matrix ual tracing of gray matter within these demarcations (Fig. 1C). To reduce (Tim) acquisition system, but the resulting images were not qualitatively variability in EPI time series due to susceptibility artifact, thresholds were different from images before the upgrade). High-resolution T1-weighted applied to ROIs to exclude voxels with a mean signal in the intensity- images were acquired using a magnetization-prepared rapid acquisition normalized (mean, 1000) EPI time series below 3000, corresponding gradient echo (MPRAGE) pulse sequence (matrix size, 256 ϫ 256; 192 approximately to a signal-to-noise (SNR) ratio of 20 (Firbank et al., 6552 • J. Neurosci., May 9, 2012 • 32(19):6550–6560 Libby et al. • Human PRC and PHC Functional Connectivity

2000). Thresholding led to the rejection of no more than 5% of voxels in any ROI. These thresholded ROIs were used as seed regions in ensuing functional connectivity analyses. White matter (WM) and CSF probability maps were generated using FMRIB’s Automated Segmentation Tool and thresholded at p(vol- ume) ϭ 1 to create WM and CSF ROIs. Functional connectivity analysis. Mean time series for all voxels within left and right seed ROIs as well as WM and CSF ROIs were extracted from individually registered prepro- cessed functional images and mean centered. Beyond initial preprocessing, functional images then underwent smoothing witha5mm full-width at half-maximum Gaussian kernel. Separate analyses were conducted using a general linear model (GLM) to estimate regions that showed significant functional connectivity with the PRC and PHC. These analyses were conducted separately because the functional connectivity profiles of closely interconnected regions (such as PRC and PHC) may be highly overlapping. Given that the GLM estimates unique contributions of each regressor of interest, including both PRC and PHC time courses in the same GLM could artificially ex- aggerate differences between the connectivity profiles of these regions. Therefore, four separate GLM analyses were run, one for each seed ROI (right or left PHC or PRC). In each GLM, the mean-centered time series for each seed ROI was included as a covariate of interest. To control for nonneuronal sources of variance, such as heart rate and respiration, WM and CSF mean-centered time series were included as covariates of no interest (Wise et al., 2004; Birn et al., 2006). Functional connectivity results maps were registered in a two-step process, first to individual subject MPRAGE images (df ϭ 6) and then to the Montreal Neu- rological Institute (MNI) 152 brain template Figure 2. A, B, Summary of functional connectivity analysis procedures for Experiment 1 (A) and Experiment 2 (B). (df ϭ 12) to prepare individual data for group- level analysis. Finally, voxelwise group-level analyses were performed. As Experiment 2: high-resolution imaging described in detail below, the group analyses were either one-sample or Data acquisition and preprocessing. Participants were scanned at the UC paired-sample t tests performed on parameter estimates derived from the Davis Imaging Research Center on a 3T Siemens Tim Trio system with a single-subject GLM analyses. All resulting group t statistic images were 32-channel phased-array head coil. Sagittal T1-weighted images were converted to (Gaussianized) z statistic images and thresholded using acquired using an MPRAGE sequence (matrix size, 256 ϫ 256; 208 slices; clusters determined by z Ͼ 2.3 and a corrected cluster significance voxel size, 1 ϫ 1 ϫ 1 mm) to localize the hippocampal formation for threshold of p Ͻ 0.05 (Worsley et al., 1996). alignment of high-resolution images. High-resolution T2-weighted Group analyses were conducted in three steps (Fig. 2A). (1) For structural images were acquired in an oblique coronal plane perpen- single-seed connectivity maps, four one-sample t tests were con- dicular to the longitudinal axis of the hippocampus using a spin-echo ducted, each assessing connectivity with a separate seed ROI. (2) For sequence (matrix size, 200 ϫ 161 mm; TR, 4200 ms; TE, 106 ms; FOV, within-seed hemispheric asymmetry maps, paired-sample t tests were 20 cm; 28 slices, interleaved; voxel size, 0.4 ϫ 0.4 ϫ 1.9 mm). Images performed, each comparing functional connectivity maps associated sensitive to BOLD contrast were acquired using a high-resolution with seeds in right and left hemispheres. These t tests were conducted gradient-echo EPI sequence (200 time points; matrix size, 128 ϫ 128 separately for seeds in PRC and PHC and yielded voxel maps reflect- mm; TR, 3000 ms; TE, 33 ms; FOV, 192 mm; 40 slices, interleaved; ing hemispheric asymmetry of the functional connectivity profile of voxel size, 1.5 ϫ 1.5 ϫ 1.9 mm) for 10 min at rest with eyes open and each seed ROI. (3) For maps of differential connectivity with PRC and lights off in the same plane centered on the hippocampus and perpen- PHC, two voxelwise paired-sample t tests were performed, each con- dicular to the longitudinal axis of the hippocampus. Coplanar trasting parameter estimates extracted from the GLM assessing func- matched-bandwidth high-resolution gradient echo EPI sequences tional connectivity with either the left or right PRC seed against (200 time points; matrix size, 128 ϫ 128 mm; TR, 3000 ms; TE, 33 ms; parameter estimates extracted from the GLM assessing connectivity FOV, 192 mm; 40 slices, interleaved; voxel size, 1.5 ϫ 1.5 ϫ 1.9 mm) with the ipsilateral PHC seed. Because resulting voxel clusters were were also acquired for registration of functional scans to structural highly extensive and connected, to describe the full pattern of results, images (Ekstrom et al., 2009). Preprocessing procedures for high- regional local maxima were identified by locating the 60 peak local resolution fMRI data were identical to methods applied to whole- maxima within each cluster (Worsley et al., 1996) and then selecting brain images in Experiment 1, described above. from these the greatest maximum for each anatomical region covered Demarcations of anatomical regions of interest. Boundaries between by the cluster. PRC, ERC, PHC, subiculum, CA1, and a CA2/CA3/DG region were de- Libby et al. • Human PRC and PHC Functional Connectivity J. Neurosci., May 9, 2012 • 32(19):6550–6560 • 6553 fined manually on individual participant high-resolution structural im- Results ages in FSLView according to Insausti et al. (1998), Duvernoy and Experiment 1: whole-brain imaging Bourgouin (1998), and Zeineh et al. (2001) (Fig. 1D). As in Experiment Our first analyses focused on separately characterizing the intrin- 1, right and left PRC and PHC ROIs were thresholded to remove voxels sic connectivity profiles of the PHC and PRC. Figure 3 shows the with low functional signal (normalized intensity of Ͻ2500, correspond- ϳ functional connectivity maps for left and right hemisphere seed ing to an SNR of 65) (Firbank et al., 2000), and these thresholded ROIs in the PRC and PHC. As seen in the figure, for both PRC masks were used as seed ROIs in ensuing functional connectivity and PHC, functional connectivity maps for seeds in right and left analyses. For analysis of differences along the longitudinal axis of the hemispheres were visually similar to one another. In general, the hippocampus, subiculum, CA1, and CA2/CA3/DG ROIs were each additionally divided into head (slices 6–12), body (slices 13–18), and PRC exhibited connectivity with a network of regions in the an- tail (slices 19–25) sections based on anatomical landmarks (Duver- terior temporal and the ventrolateral prefrontal cortices, with noy and Bourgouin, 1998). WM and CSF ROIs were created accord- considerable similarity between seeds in right and left hemi- ing to the procedure described for Experiment 1. spheres. The PHC exhibited connectivity with a network of re- Functional connectivity analysis. Functional connectivity analyses in gions that included areas in the posterior midline (retrosplenial, Experiment 2 for right and left PRC and PHC seeds were identical to posterior cingulate, and precuneus) and occipital cortex that was analyses in Experiment 1, with the following exceptions. Functional con- similar for right and left hemisphere seeds. Additionally, both nectivity volumes were registered into individual-subject structural PRC and PHC showed a high degree of connectivity across the space in FLIRT via a two-step process, first to coplanar matched- entire MTL. bandwidth images (df ϭ 6) and then to high-resolution T2 images (df ϭ The second set of analyses compared the functional connec- 6). To optimize ROI registration across individuals, linear registration tivity of seeds in right and left hemispheres separately for PRC (df ϭ 12) was performed in FLIRT to align individually registered func- and PHC (Fig. 3, bottom row). Compared with seeds in the con- tional connectivity volumes with a single participant’s high-resolution tralateral hemisphere, all seeds exhibited preferential connectiv- structural image for group analysis. Then, resulting group-registered ity with select voxels in the MTL ipsilateral to the seed, including contrast images underwent nonlinear diffeomorphic registration PRC, PHC, and anterior and posterior HF, and with select voxels (smoothness constraint, two voxels) within the MTL using the ROI- in ipsilateral cortex outside of the MTL. For connectivity with based Alignment procedure (Yassa and Stark 2009), providing a single PRC, significant asymmetries were observed in lateral temporal group MTL image reflective of individual nonlinear anatomical varia- and medial and lateral prefrontal cortex. For connectivity with tion. BOLD signal loss in the ERC due to susceptibility artifact precluded PHC, significant asymmetries were observed in medial and lat- detailed analysis of functional connectivity in this area. eral parietal and lateral prefrontal cortices. Critically, these anal- To determine the topographic patterns of functional connectivity yses revealed (1) a small number of voxels relative to one-sample within the HF associated with PHC and PRC, group-level functional connectivity profiles for each seed region were calculated with voxelwise t test results and (2) no significant voxels contralateral to any seed one-sample t tests (Fig. 2B). Resulting t statistic images were converted to region, suggesting that, for both PRC and PHC, connectivity as- (Gaussianized) z statistic images, masked to exclude voxels outside of the sociated with seeds in one hemisphere replicated connectivity MTL, and thresholded at z Ͼ 2.3 and a corrected cluster significance associated with seeds in the other hemisphere. threshold of p Ͻ 0.05 (Worsley et al., 1996). Our next analyses focused on contrasts between whole-brain To examine the distribution of PRC and PHC functional connectivity functional connectivity maps for seeds in PHC and PRC (Fig. 4). along the anterior–posterior axis of the HF, we plotted mean parameter To test directly for relative differences in whole-brain functional estimates indexing functional connectivity obtained from normalized connectivity with these two seed regions, we statistically con- individual-level PRC and PHC connectivity analyses (voxelwise one- trasted functional connectivity maps associated with PHC and sample t tests) for each slice of right and left subiculum, CA1, and CA2/ PRC seed regions from the same hemisphere. Paired t tests re- CA3/DG. To assess the differential topography of PRC versus PHC vealed distinct, bilateral pathways that differentially connected functional connectivity along the anterior–posterior axis by subfield, we with the PRC and PHC seed regions. PRC showed relatively extracted parameter estimates indexing connectivity with PRC and PHC greater functional connectivity with an anterior network that in- (from voxelwise one-sample t tests) averaged across all voxels in either cluded anterior fusiform cortex; posterior lateral and inferior head, body, or tail segments of each subfield. These PRC and PHC con- temporal cortices; temporoparietal cortex; precentral and post- nectivity estimates were submitted to repeated-measures ANOVA with central gyri; orbitofrontal cortex; dorsolateral, ventrolateral, and seed ROI (PHC vs PRC), seed hemisphere, target ROI (CA2/CA3/DG vs dorsomedial prefrontal cortices; and anterior HF. PHC showed CA1 vs subiculum), target hemisphere, and longitudinal section (head vs relatively greater functional connectivity with a posterior net- body vs tail segment of each subfield) as factors, using the Huynh–Feldt work that included medial and lateral occipital cortex, precuneus, correction for nonsphericity (Huynh and Feldt, 1976; Lecoutre, 1991). posterior cingulate cortex, pulvinar, retrosplenial cortex, and To characterize effects detected in the above ANOVA, a set of planned posterior HF. Table 1 provides local maxima defined for anatom- comparisons were performed at the level of each subfield at each longitudinal section (e.g., the effect of seed ROI within CA1 head). Initial ical regions within each network. comparisons of PRC and PHC connectivity indicated no significant dif- Experiment 2: high-resolution imaging ference in the head of CA2/CA3/DG, but slice-by-slice extractions sug- Results from Experiment 1 indicated that the PHC showed rela- gested that differential connectivity may be stronger in the anterior three slices of CA2/CA3/DG compared to other slices in the head section. tively stronger connectivity with the posterior hippocampus, and Therefore, we repeated the relevant comparison, substituting connectiv- that PRC showed relatively stronger connectivity with the poste- ity estimates extracted from only the most anterior three slices of CA2/ rior hippocampus. In Experiment 2, we used high-resolution CA3/DG for estimates from the entire head segment of this subregion. fMRI centered on the MTL to investigate intrinsic functional Additionally, because planned comparisons suggested differential PHC connectivity between PHC and PRC seeds and subfields of the HF connectivity in the tail segments of all three subfields, a further set of (Fig. 5). To characterize the topography of PRC and PHC func- comparisons determined whether differential PHC connectivity differed tional connectivity along the longitudinal axis of the HF, we plot- in magnitude between the tail segments of CA2/CA3/DG, CA1, and ted mean parameter estimates indexing connectivity with the subiculum. PRC and PHC seeds (from one-sample t tests) for each slice in the 6554 • J. Neurosci., May 9, 2012 • 32(19):6550–6560 Libby et al. • Human PRC and PHC Functional Connectivity six HF ROIs (right and left subiculum, CA1, and CA2/CA3/DG). As shown in Figure 6A, the results revealed different distributions of PRC and PHC functional connectivity across the length of the HF, and the extent of the connectivity differences along the longitudinal axis appeared to differ across the three subfields. To quantify these differences, we seg- mented each HF subfield into anatomically based head, body, and tail sections (Fig. 6B) and extracted parameter estimates indexing mean PRC and PHC functional connectivity (from one-sample t tests) across all voxels in each of these sections for each individual. A repeated- measures ANOVA of PRC and PHC connectivity estimates from each longitudinal section of CA2/CA3/DG, CA1, and subiculum revealed significant two-way interactions of seed region by longitudinal ϭ Ͻ ␧ section (F(2,28) 101.76, p 0.001, H-F ϭ 0.64) and seed region by subfield ϭ Ͻ ␧ ϭ (F(2,28) 21.33, p 0.001, H-F 1.07), and, most importantly, a significant three-way interaction of seed region by ϭ longitudinal section by subfield (F(4,56) Ͼ ␧ ϭ 8.92, p 0.001, H-F 0.74). The significant three-way interaction confirmed that differences in the connectivity of PRC and PHC along the anterior–posterior hippocampal axis differed across subfields. Follow-up analyses to break down this three-way interaction revealed that PRC connectivity was significantly greater than PHC connectivity in the head segment of ϭ Ͻ CA1 (F(1,14) 55.99, p 0.001) and subic- ϭ Ͻ ulum (F(1,14) 30.74, p 0.001) and the ϭ Ͻ body segment of CA1 (F(1,14) 6.31, p 0.05). In contrast, PHC connectivity was significantly greater than PRC connectivity in the body segment of CA2/CA3/DG ϭ Ͻ (F(1,14) 38.42, p 0.001) and subiculum ϭ Ͻ Figure 3. Whole brain analysis of functional connectivity with PRC and PHC. One-sample t test (top two rows) and left (LH) (F(1,14) 5.90, p 0.05) and the tail seg- Ͼ Ͻ ϭ Ͻ versusrighthemisphere(RH)seedpairedttest(bottomrow)whole-brainfunctionalconnectivityresults(z 2.3,pcluster 0.05) ments of CA2/CA3/DG (F(1,14) 45.45, p ϭ Ͻ mappedseparatelyforseedsinPRCandPHC.Cyan,LHseedconnectivityonly;pink,RHseedconnectivityonly;teal,LHseedgreater 0.001), CA1 (F(1,14) 5.86, p 0.05), and ϭ Ͻ than RH seed connectivity; purple, RH seed greater than LH seed connectivity. subiculum (F(1,14) 64.09, p 0.001). PRC and PHC connectivity estimates were not ference appeared to vary across subfields. An additional significantly different in CA2/CA3/DG head (Fig. 6C). repeated-measures (subfield by seed region) ANOVA re- The comparisons described above indicated that, relative to stricted to tail segments revealed a significant two-way inter- PHC, PRC showed significantly higher connectivity with the head of ϭ Ͻ ␧ ϭ the hippocampus in the subiculum and CA1. Although functional action (F(2,28) 12.26, p 0.001, H-F 1.00), and follow-up connectivity estimates for PRC and PHC seeds did not differ signif- tests revealed that preferential PHC connectivity was greater ϭ icantly in the head of CA2/CA3/ DG, slice-by-slice extractions sug- in subiculum tail compared to CA2/CA3/DG tail (F(1,14) Ͻ gested that differential connectivity may be present in the most 5.72, p 0.05), and greater in CA2/CA3/DG tail compared to ϭ Ͻ anterior slices of this subfield (Fig. 6A). Additional analysis indeed CA1 tail (F(1,14) 7.58, p 0.01). revealed that PRC connectivity was significantly greater than PHC In summary, the results of Experiment 2 converged with those connectivity within the most anterior three slices of CA2/CA3/DG of Experiment 1 to suggest a gradient of functional connectivity ϭ Ͻ (F(1,14) 4.53, p 0.05). with the PHC and PRC along the extent of the hippocampus. The With regard to the tail of the hippocampus, our analyses re- high-resolution data from Experiment 2 further indicated that vealed that each subfield tail showed greater connectivity with the this pattern differed across hippocampal subregions. Whereas PHC than with the PRC, although the magnitude of this dif- PHC showed preferential connectivity with tail segments of all Libby et al. • Human PRC and PHC Functional Connectivity J. Neurosci., May 9, 2012 • 32(19):6550–6560 • 6555

such an anterior–posterior vascular division within both hippocampus and parahippocampal gyrus is not supported by cere- brovascular studies (Marinkovic´ et al., 1991, 1992; Erdem et al., 1993; Duvernoy and Bourgouin, 1998; Huther et al., 1998). Most commonly, PRC, PHC, and hippocampus are vascularized by arteries arising from a combination of the anterior choroidal and posterior cerebral arteries. It is therefore improbable that the robust and reliable (found in both Experiment 1 and Experiment 2) anterior–posterior functional connectivity dissociation within the hippocampus arose due to differences in vascular origin between anterior and posterior MTL. Another factor that can spuriously influence resting-state functional connectivity estimates is head motion, which has the effect of inflating correlations between a seed voxel and proximal voxels (Power et al., 2011). Therefore, when the connectivity patterns of two seeds are compared within the same individual, as in the current study, motion artifact could theoretically induce preferential connectivity between each seed and the geometrically closest voxels. However, in both Experiments 1 and 2, it was not exclusively the case that a brain region showed relatively stronger functional connectivity with the seed region to which it was geometrically closest. For instance, in Experiment 1, the temporoparietal junction was preferentially functionally connected with PRC, but geometrically closer to PHC, and in Experiment 2, the body segment of CA1 was preferentially connected with PRC, but geometrically closer to PHC. This disconnect between proximity and connectivity strength argues against a motion artifact explanation, and thus simultaneous neural activity rather than simple spatial proximity is the more parsimonious explanation of the current results.

Discussion In the current study, we compared functional connectivity profiles of human PRC and PHC using both whole-brain imaging and high-resolution imaging centered on the MTL. Experiment 1 revealed that PRC showed preferential connectivity with anterior hippocampus, whereas PHC showed preferential connectivity with posterior hippocampus. High-resolution fMRI results from Experiment 2 indicated that CA1 and subiculum, but not CA2/ CA3/DG, showed the expected pattern of differential PRC connectivity across anterior hippocampus and differential PHC connectivity across posterior hippocampus, and that this anteri- or–posterior connectivity gradient was strongest in subiculum. Finally, whole-brain analyses from Experiment 1 revealed prefer- Figure 4. Comparison of cortical connectivity patterns between PRC and PHC seed regions. ential PRC connectivity with an anterior temporal and frontal Ͼ Ͻ A,B,Pairedttestwhole-brainfunctionalconnectivityresults(z 2.3,pcluster 0.05)mapped cortical network, and preferential PHC connectivity with a pos- separately for seeds in the left hemisphere (A) and right hemisphere (B). Red, PRC seed greater terior medial temporal, parietal, and occipital network. than PHC seed connectivity; blue, PHC seed greater than PRC seed connectivity. Functional connectivity within the MTL three subfields, but most strongly for subiculum, PRC showed Findings from Experiment 1 converged with those of Kahn et al. only preferential connectivity with head segments of CA1 and (2008) in showing differential connectivity of the PRC and PHC subiculum. with the anterior and posterior hippocampus. Experiment 2 ex- panded our understanding of human corticohippocampal connec- Consideration of alternate accounts tivity by allowing for separate investigation of connectivity with Although functional connectivity measures can be influenced by different hippocampal subfields. Studies in animal models suggest nonneuronal sources of BOLD signal covariance (van den Heuvel that subfields CA2/CA3/DG, CA1, and subiculum have indirect re- and Hulshoff Pol, 2010), these factors cannot sufficiently explain ciprocal connections with the PRC and PHC via the entorhinal cor- the current findings. For instance, if the anterior and posterior tex (Fig. 1A) that terminate broadly along the anterior–posterior MTL were vascularized by two separate systems of blood vessels, axis of the hippocampus (Lavenex and Amaral, 2000; Kerr et al., relative differences in blood flow could potentially yield prefer- 2007). However, in rats, additional, direct connections from PRC ential BOLD correlations between signals in PRC and anterior have been found to terminate primarily in ventral (analogous to hippocampus and PHC and posterior hippocampus. However, anterior HF in primates) CA1 and subiculum, and direct projections 6556 • J. Neurosci., May 9, 2012 • 32(19):6550–6560 Libby et al. • Human PRC and PHC Functional Connectivity

Table 1. A. Regional local maxima for PRC and PHC differential connectivity profiles LH voxels RH voxels Local maximum (MNI) z score Local maximum (MNI) z score xyz xyz LPRC Ͼ LPHC Angular gyrus (BA 39) Ϫ40 Ϫ48 50 3.92 † 52 Ϫ48 28 3.88 ◊ Anterior hippocampus Ϫ24 Ϫ12 Ϫ30 4.51 † 22 Ϫ4 Ϫ26 3.31* Anterior inferior temporal gyrus (BA 20) Ϫ56 Ϫ32 Ϫ24 5.07 † 64 Ϫ14 Ϫ28 4.2* Frontal polar cortex (BA 10) Ϫ44 58 Ϫ18 3.19 ‡ 38 60 Ϫ10 3.11 ◊ Fusiform cortex (BA 20) Ϫ42 Ϫ14 Ϫ30 4.95 † 40 Ϫ18 Ϫ28 4.05* Inferior frontal gyrus (BA 46) Ϫ58 20 Ϫ2 4.15 † 54 38 2 3.66 ◊ Lateral postcentral gyrus (BA 40) Ϫ44 Ϫ36 52 4.09 † 42 Ϫ46 42 3.24 ◊ Lateral precentral gyrus (BA4) Ϫ34 Ϫ20 54 3.86 † Lateral precentral gyrus (BA6) Ϫ52 4 12 4.62 † 60 4 4 4.47 ◊ Orbitofrontal cortex (BA 11/47) Ϫ16 24 Ϫ20 4.25 ‡ 24 12 Ϫ24 3.85* Posterior middle temporal gyrus (BA 21) Ϫ64 Ϫ36 Ϫ10 4.15 † 54 Ϫ2 Ϫ32 3.26 ◊ Posterior superior temporal gyrus (BA 22) Ϫ66 Ϫ36 24 4.46 † 66 Ϫ44 8 3.89 ◊ Perirhinal cortex Ϫ34 Ϫ10 Ϫ32 4.88 † 30 Ϫ12 Ϫ36 3.91* Temporal polar cortex (BA 38) Ϫ44 4 Ϫ42 3.99 † 38 20 Ϫ40 3.43* Temporoparietal cortex (BA 39/40/22) Ϫ66 Ϫ36 24 4.46 † 60 Ϫ40 34 4.3 ◊ Ventrolateral prefrontal cortex (BA 44/45) Ϫ54 12 16 4.83 † 54 18 12 4.17 ◊ RPRC Ͼ RPHC Angular gyrus (BA 39) 48 Ϫ36 44 3.6 † Anterior hippocampus 28 Ϫ12 Ϫ24 3.47 † Anterior inferior temporal gyrus (BA 20) 54 Ϫ12 Ϫ30 4.54 † Dorsolateral prefrontal cortex (BA 9) Ϫ24 60 24 4.22 ‡ 18 58 24 3.6 † Dorsomedial prefrontal cortex (BA 8) Ϫ2 Ϫ60 34 3.62 ‡ Frontal polar cortex (BA 10) 40 60 Ϫ2 3.79 † Fusiform cortex (BA 20) 54 Ϫ12 Ϫ30 4.54 † Inferior frontal gyrus (BA 47) 56 26 Ϫ8 4.5 † Lateral precentral gyrus (BA 6) 54 4 10 4.07 † Medial prefrontal cortex (BA 8) Ϫ2 60 34 3.62 ‡ Orbitofrontal cortex (BA 11/47) Ϫ616Ϫ22 3.92 ‡ 822Ϫ20 3.47 † Postcentral gyrus (BA 4) 62 Ϫ10 16 3.46 † Posterior middle temporal gyrus (BA 21) 70 Ϫ38 Ϫ10 4.34 † Posterior superior temporal gyrus (BA 22) Ϫ62 Ϫ34 14 4.01 † Perirhinal cortex 40 Ϫ14 Ϫ30 4.11 † Rostrolateral prefrontal cortex (BA 10) 38 60 Ϫ12 3.71 † Temporal polar cortex (BA 38) 34 22 Ϫ36 3.97 † Ventrolateral prefrontal cortex (BA 44/45) Ϫ56 6 18 3.78 † 56 26 Ϫ8 4.5 † LPHC Ͼ LPRC Lateral occipital cortex (BA 19) Ϫ38 Ϫ82 28 4.55 † 16 Ϫ98 20 4.15 † Medial posterior occipital cortex (BA 18) Ϫ2 Ϫ78 Ϫ2 4.9 † 6 Ϫ58 14 4.43 † Occipital pole (BA 17) Ϫ8 Ϫ58 Ϫ30 4.38 † 8 Ϫ102 16 4.45 † Parahippocampal cortex Ϫ14 Ϫ50 Ϫ6 4.72 † 18 Ϫ46 Ϫ4 5.01 † Posterior cingulate cortex (BA 29) Ϫ8 Ϫ50 14 4.74 † 8 Ϫ46 16 4.31 † Posterior hippocampus Ϫ20 Ϫ30 Ϫ8 4.66 † 20 Ϫ30 Ϫ6 5.35 † Posterior thalamus Ϫ20 Ϫ32 Ϫ2 3.82 † 22 Ϫ32 2 3.92 † Precuneous (BA 7) Ϫ14 Ϫ60 18 4.59 † 18 Ϫ68 24 4.89 † Retrosplenial cortex (BA 30) Ϫ8 Ϫ50 14 4.74 † 8 Ϫ58 4 4.81 † RPHC Ͼ RPRC Lateral occipital cortex (BA 19) Ϫ40 Ϫ86 24 4.14 † Medial posterior occipital cortex (BA 18) 14 Ϫ72 8 4.21 † Occipital pole (BA 17) Ϫ16 Ϫ96 22 4.28 † 14 Ϫ88 4 4.22 † Parahippocampal cortex Ϫ12 Ϫ42 Ϫ8 4.42 † 22 Ϫ32 Ϫ8 5.56 † Posterior cingulate cortex (BA 29) Ϫ4 Ϫ46 4 4.33 † 10 Ϫ44 10 4.13 † Posterior hippocampus Ϫ20 Ϫ30 Ϫ2 4.88 † 18 Ϫ36 0 5.92 † Posterior thalamus Ϫ20 Ϫ34 0 4.88 † 22 Ϫ30 6 5.03 † Precuneus (BA 7) Ϫ12 Ϫ50 40 3.26 ‡ 18 Ϫ52 36 3.61 ‡ Retrosplenial cortex (BA 30) Ϫ16 Ϫ52 Ϫ4 4.26 † 22 Ϫ46 0 5.3 † LH, Left hemisphere; RH, right hemisphere. Local maxima were defined for anatomical regions included in each cluster. Symbols indicate the extent of the cluster from which each local maximum was obtained: LPRC Ͼ LPHC, †250.42 cm 3, ‡28.26 cm 3, ◊86.04 cm 3, *35.60 cm 3; RPRC Ͼ RPHC, †199.84 cm 3, ‡25.62 cm 3; LPHC Ͼ LPRC, †444.72 cm 3; RPHC Ͼ RPRC, †433.26 cm 3, ‡9.66 cm 3. from PHC terminate primarily in dorsal (analogous to posterior HF ilar pattern in human functional connectivity such that PRC showed in primates) CA1 and subiculum, whereas CA2/CA3/DG does not stronger functional connectivity with anterior CA1 and subiculum, receive direct input from PRC or PHC (Naber et al., 1999, 2001; whereas PHC showed stronger functional connectivity with poste- Witter et al., 2000; Furtak et al., 2007). Our findings revealed a sim- rior CA1 and subiculum. Conversely, we found that this anterior– Libby et al. • Human PRC and PHC Functional Connectivity J. Neurosci., May 9, 2012 • 32(19):6550–6560 • 6557

ferential involvement of the anterior and posterior hippocampi in episodic memory encoding and retrieval (Lepage et al., 1998), but consistent differences have not been observed (Schacter et al., 1999; Schacter and Wagner, 1999). More recent research has indicated that the human posterior hippocampus shows preferential involvement in processing of spatial or contextual information (Awipi and Dava- chi, 2008; Lee et al., 2008; Duarte et al., 2011; Liang et al., 2012), whereas the anterior hippocampus may be preferentially involved in memory for faces (Lee et al., 2008) and affective stimuli (Murty et al., 2010). However, this pattern has not held in all studies, as some findings suggest a domain-general role for the anterior hippocampus (Chua et al., 2007; Awipi and Davachi, 2008; Liang et al., 2012). The current results indicate that some prog- ress toward this issue might be gained by separately considering the functional contributions of different hippocampal subfields along the longitudinal axis.

Functional connectivity with neocortex Comparison of functional connectivity profiles across the whole brain revealed that PRC and PHC were differentially associated with two distinct neocortical networks. PRC connected with an anterior network that included anterior lateral temporal and orbital prefrontal regions. PHC connected with a posterior cortical network that included the retrosplenial, posterior cingulate, and medial parietal cortex, as well as early visual areas in the occipital and posterior temporal cortices. These results are consistent with the major findings by Kahn et al. (2008), who reported different connectivity patterns for PRC and PHC in visual and visuospatial regions and medial PFC. However, we have extended PRC Figure 5. High-resolution analysis of hippocampal functional connectivity with PRC and PHC seed regions. A, B, One-sample t test and PHC connectivity profiles to include ad- Ͼ Ͻ high-resolutionfunctionalconnectivityresults(z 2.3,pcluster 0.05)mappedseparatelyforseedsinPRC(abovethediagonal)andPHC ditional regions implicated by animal models (belowthediagonal).Selectedslicesaredistributedevenlyacrossthelongitudinalaxisofthehippocampusandrepresentativeoftheoverall of anatomical connectivity, such as auditory spatial pattern of results. Cyan, Left hemisphere seed only; pink, right hemisphere seed only. Slices 6–12 contain HF head, PRC, and ERC; and somatosensory areas (Burwell and Ama- slices 13–19 contain HF body and anterior PHC; slices 20–25 contain HF tail and posterior PHC. The left hemisphere is on left. ral, 1998a; Burwell, 2000; Agster and Burwell, 2009). posterior connectivity gradient was less robust in CA2/CA3/DG, Many accounts of the functional organization of the MTL focus which could be consistent with neuroanatomical data indicating that on relative differences between dorsal and ventral stream visual in- these subfields lack direct connections with PRC or PHC. puts to the PRC and PHC (Davachi, 2006; Eichenbaum et al., 2007; These functional connectivity results complement findings of Barense et al., 2010; Diana et al., 2010; Montaldi and Mayes, 2010; functional heterogeneity along the longitudinal axis of the hip- Ranganath, 2010). However, the more striking pattern apparent in pocampus in both animals and humans. For instance, behavioral our results, as well as in the neuroanatomical literature, is that the lesion and electrophysiological work in rats and monkeys sup- PRC and PHC are differentially connected with two largely poly- port a role for the dorsal/posterior hippocampus in spatial mem- modal networks. For instance, in addition to visual areas, PRC con- ory (Colombo et al., 1998; Moser and Moser, 1998), whereas the nected preferentially with auditory and somatosensory regions. ventral hippocampus in rodents has been implicated in anxiety- Furthermore, the main components of both networks are poly- related behaviors (for review, see Bannerman et al., 2004; Fan- modal association cortices connected with PRC and PHC by major selow and Dong, 2010). Evidence for functional differentiation white matter tracts. The perirhinal, temporopolar, and orbitofrontal between the anterior and posterior hippocampus in humans has cortices correspond to a cortical network that is interconnected via been more controversial; some researchers have argued for dif- the uncinate fasciculus, whereas the parahippocampal, retrosplenial, 6558 • J. Neurosci., May 9, 2012 • 32(19):6550–6560 Libby et al. • Human PRC and PHC Functional Connectivity and medial and ventral parietal cortices correspond to a cortical network that is interconnected via the cingulum bundle (Kondo et al., 2005). These connectivity differences may be relevant to our understanding of disease (Seeley et al., 2009). Connections of the PRC (perirhinal, anterior inferior temporal, and temporopolar cortices) are heavily affected by semantic dementia (Hodges and Patter- son, 2007; Rohrer et al., 2011), whereas the posterior PHC system is less affected by this condition. In contrast, Alzheimer’s disease disproportionally affects connections of the PHC (parahippocampal, retrosplenial, and medial parietal cortices), although PRC pathology is also seen (Boxer et al., 2003; Buckner et al., 2005; Rabinovici et al., 2007). Semantic dementia is typically characterized by severe deficits in knowledge about people and objects (Murre et al., 2001; Lee et al., 2007), whereas early Alzheimer’s disease is associated with relatively more severe deficits in episodic memory (Nestor et al., 2006) and scene processing (Lee et al., 2007), suggesting that these two systems may support distinct behavioral functions. Functional imaging data also suggest that the cortical networks that are differentially affiliated with the PRC and PHC have divergent functional characteristics. Whereas the PRC and ventral temporopolar cortex have been linked to familiarity-based item recognition (Brown and Aggleton, 2001; Diana et al., 2007; Eichenbaum et al., 2007), fine-grained object discriminations (Pihlajama¨ki et al., 2005; Lee et al., 2008; Figure 6. Functional connectivity gradients along the longitudinal hippocampal axis differ between hippocampal subfields. Barense et al., 2010), and access to abstract Red, Connectivity with PRC seed; blue, connectivity with PHC seed. Error bars denote standard error across participants. Connec- semantic knowledge (Taylor et al., 2006; tivity patterns were consistent for seeds in right and left hemispheres and for extractions from right and left hippocampus; Hodges and Patterson, 2007), PHC and ret- therefore, for display purposes, connectivity estimates were collapsed across seed and extraction hemispheres. A, Parameter rosplenial function has been linked to recol- estimates indexing connectivity extracted from each slice along the anterior–posterior axis of the hippocampus for each subfield. lection of context information (Davachi, Dashed black lines delineate head, body, and tail segments of each subfield used for repeated-measures ANOVA. B, Sagittal view 2006; Diana et al., 2008), simulation of epi- of the longitudinal axis of the hippocampus, with head, body, and tail demarcated. C, Mean parameter estimates indexing sodes (Schacter et al., 2007), scene percep- connectivity averaged across all voxels in hippocampal head, body, and tail for each subfield. Asterisks indicate significant differences in PRC and PHC connectivity estimate for a given segment. *p Ͻ 0.05 (red asterisks, PRC connectivity greater than PHC tion and imagery (Epstein, 2008; Litman et connectivity; blue asterisks, PHC connectivity greater than PRC connectivity). N.S., Not significant. al., 2009; Vann et al., 2009; Staresina et al., 2011), and spatial navigation (Ekstrom and anatomically interconnected and typically share vascular origin Bookheimer, 2007; Spreng et al., 2009; Vann et al., 2009). Put into (Duvernoy and Bourgouin, 1998; Huther et al., 1998), one might context with evidence from brain anatomy, disease, and function, expect this technique to reveal largely similar functional connectivity the cortical areas that show differential connectivity with PRC and profiles for the two regions. We nonetheless observed robust differ- PHC may be described as two distinct, polymodal, large-scale neural systems that support different forms of memory-guided behavior ences in functional connectivity profiles of PHC and PRC that are (Kahn et al., 2008). incongruent with effects due to motion (Power et al., 2011) or vascular artifact, consistent with the view that these regions are func- Limitations and future directions tionally distinct (Eacott and Gaffan, 2005; Davachi, 2006; Available evidence indicates that BOLD resting-state functional con- Eichenbaum et al., 2007; Lee et al., 2008; Montaldi and Mayes, 2010; nectivity corresponds well with structural connectivity, as indicated Ranganath, 2010). Further insights into the anatomical bases of by tract tracing in animals (Vincent et al., 2007) and diffusion tensor functional connectivity differences between PRC and PHC might be imaging (DTI) in humans (Damoiseaux and Greicius, 2009; Gre- gained in future studies that combine resting-state functional con- icius et al., 2009; Honey et al., 2009). BOLD resting-state functional nectivity analysis of fMRI data with connectivity profiles obtained connectivity analyses may be overly inclusive, however, such that from DTI data (Greicius et al., 2009). functional connectivity is sensitive to both direct and indirect con- Another issue that should be considered in future research is nections (Honey et al., 2009). Given that PRC and PHC are both whether PHC and PRC show preferential connectivity with dif- Libby et al. • Human PRC and PHC Functional Connectivity J. Neurosci., May 9, 2012 • 32(19):6550–6560 • 6559 ferent sections of ERC, as might be suggested by anatomical stud- High-resolution fMRI reveals match enhancement and attentional mod- ies in the rat (Burwell and Amaral, 1998b) and monkey (Suzuki ulation in the human medial temporal lobe. J Cogn Neurosci 23:670–682. and Amaral, 1994a). Unfortunately, signal loss due to suscepti- Duvernoy HM, Bourgouin P (1998) The human hippocampus: functional anatomy, vascularization and serial sections with MRI, Ed 2. New York: bility artifact fundamentally limited our ability to detect effects in Springer. the ERC. Thus, an important challenge to be addressed in future Eacott MJ, Gaffan EA (2005) The roles of perirhinal cortex, postrhinal cor- resting-state fMRI and DTI studies will be to obtain high- tex, and the fornix in memory for objects, contexts, and events in the rat. resolution data from ERC (Yassa et al., 2011). Q J Exp Psychol B 58:202–217. 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